Cocaine and Zolmitriptan

NCT05019430 | Completed Early Phase 1 Results FDA Drug

• 2 other identifiers: BED In 42R01DA052203
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

Cocaine potently inhibits the reuptake of serotonin (5-HT). Increased synaptic 5-HT resulting from this reuptake inhibition activates multiple 5-HT receptor subtypes. Some of these receptor subtypes have been implicated in the abuse-related effects of cocaine, including its primary reinforcing effects (i.e., cocaine taking behavior). 5-HT1b receptors, which are autoreceptors on 5-HT nerve endings that regulate 5-HT release and heteroreceptors that also mediate other neurotransmitter release, play a particularly important role in cocaine effects, likely because they are highly expressed in the mesocorticolimbic system. The 5-HT1b system displays profound dysregulation during both active cocaine use and abstinence. Initial preclinical research showed that selective 5-HT1b agonists enhanced the reinforcing and locomotor effects of cocaine during ongoing cocaine administration, but subsequent research showed that these agents robustly attenuated reinstatement of cocaine- and cue-primed cocaine seeking behavior. These findings have been replicated in rigorously conducted studies using multiple schedules of reinforcement and negative sucrose reinforcement controls across laboratories. Notably, though, these preclinical studies used compounds not approved for use in humans, hindering translation. Recently published data show that zolmitriptan, a commercially available selective 5-HT1b agonist migraine medication, also selectively attenuates the reinforcing and other abuse-related effects of cocaine, regardless of stage of use (i.e., ongoing or extinguished cocaine self-administration). Although a robust preclinical literature supports the premise that 5-HT1b activation reduces a number of cocaine-associated behaviors (e.g., self-administration, cocaine seeking), this area remains unstudied in humans. The overarching goal of this project is to advance these promising preclinical findings, specifically those with zolmitriptan, to a clinical population, thereby demonstrating that the 5-HT1b system plays a key role in the effects of cocaine in humans

Conditions

Cocaine Use Disorder

Outcome Measures

Primary Outcomes (1)

• Reinforcing Effects of Cocaine

  Number of Times Subjects Choose Cocaine (Maximum of 5 Choices) Over Money

  Over approximately four hours on each experimental session day, which generally occurred on Days 5-7, 13-15, 21-23 and 29-31 of inpatient admission.

Study Arms (4)

Placebo

PLACEBO COMPARATOR

Subjects will be maintained on oral placebo. Cocaine will be administered acutely during placebo maintenance. Placebo will be administered acutely during placebo maintenance.

Drug: Cocaine; Drug: Placebo oral capsule

Zolmitriptan Dose 1

EXPERIMENTAL

Subjects will be maintained on oral zolmitriptan dose 1. Cocaine will be administered acutely during zolmitriptan dose 1 maintenance. Placebo will be administered acutely during zolmitriptan dose 1 maintenance.

Drug: Cocaine

Zolmitriptan Dose 2

EXPERIMENTAL

Subjects will be maintained on oral zolmitriptan dose 2. Cocaine will be administered acutely during zolmitriptan dose 2 maintenance. Placebo will be administered acutely during zolmitriptan dose 2 maintenance.

Drug: Cocaine; Drug: Zolmitriptan

Zolmitriptan Dose 3

EXPERIMENTAL

Subjects will be maintained on oral zolmitriptan dose 3. Cocaine will be administered acutely during zolmitriptan dose 3 maintenance. Placebo will be administered acutely during zolmitriptan dose 3 maintenance.

Drug: Cocaine; Drug: Zolmitriptan

Interventions

Cocaine DRUG

The pharmacodynamic effects of cocaine will be determined during maintenance on placebo and zolmitriptan.

Placebo; Zolmitriptan Dose 1; Zolmitriptan Dose 2; Zolmitriptan Dose 3

Placebo oral capsule DRUG

The pharmacodynamic effects of placebo will be determined.

Placebo

Zolmitriptan DRUG

The pharmacodynamic effects of zolmitriptan maintenance will be determined.

Zolmitriptan Dose 2; Zolmitriptan Dose 3

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Recent cocaine use

You may not qualify if:

• Abnormal screening outcome (e.g., ECG, blood chemistry result) that study physicians deem clinically significant
• Current or past histories of substance use disorder that are deemed by the study physicians to interfere with study completion
• History of serious physical disease, current physical disease, impaired cardiovascular functioning, chronic obstructive pulmonary disease, history of seizure or current or past histories of serious psychiatric disorder that in the opinion of the study physician would interfere with study participation will be excluded from participation
• Females not currently using effective birth control
• Contraindications to cocaine or zolmitriptan

Sponsors & Collaborators

• William Stoops: lead
• National Institute on Drug Abuse (NIDA): collaborator

Study Sites (1)

University of Kentucky

Lexington, Kentucky, 40507, United States

Location

MeSH Terms

Interventions

Cocaine; zolmitriptan

Intervention Hierarchy (Ancestors)

Tropanes; Azabicyclo Compounds; Aza Compounds; Organic Chemicals; Alkaloids; Heterocyclic Compounds; Bridged Bicyclo Compounds, Heterocyclic; Heterocyclic Compounds, Bridged-Ring

Results Point of Contact

• Title: William W. Stoops
• Organization: University of Kentucky

william.stoops@uky.edu

8592575388

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: August 13, 2021
• First Posted: August 24, 2021
• Study Start: October 15, 2021
• Primary Completion: January 9, 2025
• Study Completion: January 9, 2025
• Last Updated: August 5, 2025
• Results First Posted: August 5, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)